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Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis (iCaD)

Primary Purpose

Colitis

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Infliximab
Methylprednisolone
Prednisolone
Sponsored by
Odense University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Untreated mCTCAE grade 2-4 diarrhoea or colitis, or persistent mCTCAE grade 2 diarrhoea after administration of loperamide or equivalent for mCTCAE grade ≤ 2 diarrhoea No signs of colonic perforation or infection Age ≥ 18 Understands the nature and purpose of the study and the study procedures and has signed informed consent Is able to read, understand, and complete questionnaires and daily components of the patient Diary for the study period Histologically confirmed malignant solid tumours Treatment with immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 or anti-PD-L1) within the past 12 weeks. Immune checkpoint inhibitors can be administered as single agents or as combination therapy with anti-CTLA-4 and anti-PD-1 No probability of a concomitant treatment (e.g. laxatives) other than the immune checkpoint inhibitor being the causal drug for the colitis or diarrhoea Prior treatment with immune checkpoint inhibitors is allowed Usage of prednisolone ≤ 10 mg daily for non irAE is allowed Diagnostic work up including screening for viral hepatic infection and QuantiFERON-TB for mycobacterium tuberculosis must be requisitioned but will not need to be reported prior to study enrolment Women of child bearing potential must have a negative serum (preferred) or urine pregnancy test within 72 hours prior to registration. Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the study treatment: for at least 6 months after the last study treatment, or depending on the duration antineoplastic treatment Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomized partner Sexual abstinence Exclusion Criteria Prior history of inflammatory bowel disease, colitis, or diarrhoea requiring treatment with any corticosteroid, or any other immunosuppressant medication Prior history of recurrent bowel disease including symptomatic diverticulosis Current positive testing for Clostridium difficile or other colonic infection Current bacterial infection requiring antibiotic treatment, or systemic fungal infection Ongoing antibiotic treatment for any reason Treatment with systemic corticosteroids within the last four weeks prior to study enrolment (daily usage of prednisolone ≤ 10 mg for non irAE conditions is accepted) Concurrent immune-related adverse events requiring immunosuppressant medication of any kind Known hypersensitivity or contraindications to systemic corticosteroids or infliximab Prior history of viral hepatitis with a positive viral load, known untreated mycobacterium tuberculosis, or known active herpes zoster infection

Sites / Locations

  • Department of Oncology, Aalborg University Hospital
  • Department of Oncology Odense University HospitalRecruiting
  • The Royal Marsden Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard of care - Methylprednisolone

Treatment with infliximab

Arm Description

Subjects are hospitalised Day 1 and for at least 4 days. It is accepted that participating centres handle the subjects on an outpatient basis as long as all study requirements are met. Methylprednisolone 80 mg intravenously (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight < 40 or > 80 kg) will be administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. During tapering, if ir-colitis/diarrhoea increases from grade 2 to ≥ grade 3, or from grade < 2 to ≥ grade 2, re-assessment including diagnostic workup will be performed, and the patient will be evaluated for rescue infliximab.

Infliximab will be administered Day 1 or latest Day 2 (within 48 hours). Infliximab infusion is handled as standard by skilled staff. A second dose of infliximab will be administered if ir-colitis/diarrhoea has not resolved to grade ≤ 2 on Day 7. Methylprednisolone 80 mg (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight < 40 or > 80 kg) intravenously is co-administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. Initial dosage of infliximab is 5 mg/kg. Dosage of infliximab for subjects referred to a second dose of infliximab will be left to the discretion of the treating physician. In the event of failure of infliximab, second line biological immunosuppressant treatment will also be left to the discretion of the treating physician.

Outcomes

Primary Outcome Measures

Time (days) to persistent modified CTCAE grade ≤ 1 ir-colitis/diarrhoea.
Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more with no increase in corticosteroid intake

Secondary Outcome Measures

Proportion of study subjects with grade ≤ 1 ir-colitis/diarrhoea at 72 hours.
Proportion of study subjects with persistent grade ≤ 1 ir-colitis/diarrhoea at three weeks.
Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more
Proportion of study subjects with a corticosteroid-free clinical remission (grade ≤ 1 ir-colitis/diarrhoea) after seven weeks.
Proportion of study subjects requiring rescue immunosuppressive medication
Arm A (initial corticosteroid only): infliximab if no improvement to grade ≤ 2 ir-colitis/diarrhoea after 3 days (time frame: seven weeks); Arm B (initial infliximab): second dose infliximab according to physicians decision if no improvement to grade ≤ 2 ir-colitis/diarrhoea after seven days
Cumulative corticosteroid exposure
QoL by means of EORTC-QLQ-C30
A 30-item questionaire developed to assess the quality of life of cancer patients. Item 1-28 is scaled in a 4 scale score from 'not at all' to 'very much'. Item 29-30 is a numeric rating scale from 1 to 7 assessing overall health/quality of life. One denotes very poor and 7 denotes excellent. Measure: changes in quality of life
QoL by means of selected PRO-CTCAE items
A 8 item questionnaire assessing bowel related issues. The scales ranges from eg: Yes/No Never/rarely/occasionally/frequently/almost constant None/mild/moderate/severe/very severe Not at all/a little bit/ somewhat/quit a bit/very much Measure: changes in bowel related symptoms
Proportion of study subjects with treatment related adverse events as assessed by CTCAE v5.0
Proportion of study subjects with colectomy or colitis-specific mortality

Full Information

First Posted
June 14, 2023
Last Updated
August 22, 2023
Sponsor
Odense University Hospital
Collaborators
Aalborg University Hospital, Royal Marsden NHS Foundation Trust
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1. Study Identification

Unique Protocol Identification Number
NCT05947669
Brief Title
Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis
Acronym
iCaD
Official Title
Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis: a Multinational, Randomised, Open Label, Phase III Trial - The iCaD Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 22, 2023 (Actual)
Primary Completion Date
September 2026 (Anticipated)
Study Completion Date
September 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Odense University Hospital
Collaborators
Aalborg University Hospital, Royal Marsden NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to assess whether the early introduction of biological treatment with a TNF-alpha inhibitor (infliximab) in addition to corticosteroids for severe ir-colitis/diarrhoea will reduce the time to grade ≤ 1 ir-colitis/diarrhoea compared to corticosteroids alone in patients scheduled for ICI treatment for solid tumors and untreated mCTCAE grade 2-4 diarrhoea or colitis. The main question it aims to answer is: • Can an early introduction of biological treatment with a TNF-alpha inhibitor (infliximab) in addition to corticosteroids reduce the time to grade ≤ 1 ir-colitis/diarrhoea compared to corticosteroids alone. Participants will be randomised 1:1: Arm A: All patients will receive same dose of methylprednisolone i.v. daily. Arm B: Patients allocated to Arm B will in addition receive infliximab i.v. day 1 or 2. Study patients are evaluated with blood samples, faecal samples and by sigmoidoscopy. Procedures are performed before randomisation and as part of follow up.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
195 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of care - Methylprednisolone
Arm Type
Active Comparator
Arm Description
Subjects are hospitalised Day 1 and for at least 4 days. It is accepted that participating centres handle the subjects on an outpatient basis as long as all study requirements are met. Methylprednisolone 80 mg intravenously (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight < 40 or > 80 kg) will be administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. During tapering, if ir-colitis/diarrhoea increases from grade 2 to ≥ grade 3, or from grade < 2 to ≥ grade 2, re-assessment including diagnostic workup will be performed, and the patient will be evaluated for rescue infliximab.
Arm Title
Treatment with infliximab
Arm Type
Experimental
Arm Description
Infliximab will be administered Day 1 or latest Day 2 (within 48 hours). Infliximab infusion is handled as standard by skilled staff. A second dose of infliximab will be administered if ir-colitis/diarrhoea has not resolved to grade ≤ 2 on Day 7. Methylprednisolone 80 mg (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight < 40 or > 80 kg) intravenously is co-administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. Initial dosage of infliximab is 5 mg/kg. Dosage of infliximab for subjects referred to a second dose of infliximab will be left to the discretion of the treating physician. In the event of failure of infliximab, second line biological immunosuppressant treatment will also be left to the discretion of the treating physician.
Intervention Type
Drug
Intervention Name(s)
Infliximab
Intervention Description
Infliximab is available in vials of 100 mg with pharmaceutical form of concentrate for solution for infusion. Participating sites will ensure availability of infliximab as part of the hospital's standard supply for use in the study.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Intervention Description
Methylprednisolone is available in vials of 40 mg. Methylprednisolone is a drug used for standard treatment first line for ir-colitis or diarrhoea CTCAE grade ≥ 3. Participating sites will ensure availability of methylprednisolone for use in the study as part of the hospitals standard supply.
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Description
Prednisolone is available in tablets of 25 or 5 mg. Oral corticosteroids are internationally recommended as initial treatment for ir-colitis and ir-diarrhoea CTCAE grade 2 [24-27]. Participating sites will ensure availability of prednisolone for use in the study as part of the hospitals' standard supply.
Primary Outcome Measure Information:
Title
Time (days) to persistent modified CTCAE grade ≤ 1 ir-colitis/diarrhoea.
Description
Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more with no increase in corticosteroid intake
Time Frame
From the first day of grade ≤ 1 ir-colitis/diarrhoea of that period (time frame: seven weeks)
Secondary Outcome Measure Information:
Title
Proportion of study subjects with grade ≤ 1 ir-colitis/diarrhoea at 72 hours.
Time Frame
Time frame: 72 hours
Title
Proportion of study subjects with persistent grade ≤ 1 ir-colitis/diarrhoea at three weeks.
Description
Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more
Time Frame
The event will be calculated from the first day of grade ≤ 1 ir-colitis/diarrhoea of that period (time frame: three weeks)
Title
Proportion of study subjects with a corticosteroid-free clinical remission (grade ≤ 1 ir-colitis/diarrhoea) after seven weeks.
Time Frame
Time frame: seven weeks
Title
Proportion of study subjects requiring rescue immunosuppressive medication
Description
Arm A (initial corticosteroid only): infliximab if no improvement to grade ≤ 2 ir-colitis/diarrhoea after 3 days (time frame: seven weeks); Arm B (initial infliximab): second dose infliximab according to physicians decision if no improvement to grade ≤ 2 ir-colitis/diarrhoea after seven days
Time Frame
Time frame: seven days
Title
Cumulative corticosteroid exposure
Time Frame
Time frame: seven weeks
Title
QoL by means of EORTC-QLQ-C30
Description
A 30-item questionaire developed to assess the quality of life of cancer patients. Item 1-28 is scaled in a 4 scale score from 'not at all' to 'very much'. Item 29-30 is a numeric rating scale from 1 to 7 assessing overall health/quality of life. One denotes very poor and 7 denotes excellent. Measure: changes in quality of life
Time Frame
Change in score from baseline to 3, 12, 24, and 52 weeks after randomisation
Title
QoL by means of selected PRO-CTCAE items
Description
A 8 item questionnaire assessing bowel related issues. The scales ranges from eg: Yes/No Never/rarely/occasionally/frequently/almost constant None/mild/moderate/severe/very severe Not at all/a little bit/ somewhat/quit a bit/very much Measure: changes in bowel related symptoms
Time Frame
Change in score from baseline to 3, 12, 24, and 52 weeks after randomisation
Title
Proportion of study subjects with treatment related adverse events as assessed by CTCAE v5.0
Time Frame
Time frame: 12 weeks
Title
Proportion of study subjects with colectomy or colitis-specific mortality
Time Frame
Time frame: seven weeks
Other Pre-specified Outcome Measures:
Title
Proportion of study subjects with recurrence of ir-colitis/diarrhoea on subsequent reintroduction of ICI.
Time Frame
Timeframe: Up to 24 weeks
Title
Subgroup analyses stratified for ipilimumab containing ICI for time (days) to persistent grade ≤ 1 ir-colitis/diarrhoea.
Description
Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more.
Time Frame
week 3
Title
Progression Free Survival stratified by cancer type
Time Frame
Time frame: duration of time from start of randomisation to time of progression or death, whichever occurs first or up to 24 months
Title
Overall Survival stratified by cancer type
Time Frame
Time frame: the duration of time from start of randomisation to time of death or up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Untreated mCTCAE grade 2-4 diarrhoea or colitis, or persistent mCTCAE grade 2 diarrhoea after administration of loperamide or equivalent for mCTCAE grade ≤ 2 diarrhoea No signs of colonic perforation or infection Age ≥ 18 Understands the nature and purpose of the study and the study procedures and has signed informed consent Is able to read, understand, and complete questionnaires and daily components of the patient Diary for the study period Histologically confirmed malignant solid tumours Treatment with immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 or anti-PD-L1) within the past 12 weeks. Immune checkpoint inhibitors can be administered as single agents or as combination therapy with anti-CTLA-4 and anti-PD-1 No probability of a concomitant treatment (e.g. laxatives) other than the immune checkpoint inhibitor being the causal drug for the colitis or diarrhoea Prior treatment with immune checkpoint inhibitors is allowed Usage of prednisolone ≤ 10 mg daily for non irAE is allowed Diagnostic work up including screening for viral hepatic infection and QuantiFERON-TB for mycobacterium tuberculosis must be requisitioned but will not need to be reported prior to study enrolment Women of child bearing potential must have a negative serum (preferred) or urine pregnancy test within 72 hours prior to registration. Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the study treatment: for at least 6 months after the last study treatment, or depending on the duration antineoplastic treatment Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomized partner Sexual abstinence Exclusion Criteria Prior history of inflammatory bowel disease, colitis, or diarrhoea requiring treatment with any corticosteroid, or any other immunosuppressant medication Prior history of recurrent bowel disease including symptomatic diverticulosis Current positive testing for Clostridium difficile or other colonic infection Current bacterial infection requiring antibiotic treatment, or systemic fungal infection Ongoing antibiotic treatment for any reason Treatment with systemic corticosteroids within the last four weeks prior to study enrolment (daily usage of prednisolone ≤ 10 mg for non irAE conditions is accepted) Concurrent immune-related adverse events requiring immunosuppressant medication of any kind Known hypersensitivity or contraindications to systemic corticosteroids or infliximab Prior history of viral hepatitis with a positive viral load, known untreated mycobacterium tuberculosis, or known active herpes zoster infection
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sören K. Petersen, MD
Phone
0045 2046 5726
Email
soeren.kjaer@rsyd.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christina H. Ruhlmann, PhD
Organizational Affiliation
Department of Oncology, OUH
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Oncology, Aalborg University Hospital
City
Aalborg
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charlotte Aaquist Haslund, MD
Facility Name
Department of Oncology Odense University Hospital
City
Odense
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christina H. Ruhlmann, PhD
Phone
0045 2231 4446
Email
christina.ruhlmann@rsyd.dk
Facility Name
The Royal Marsden Hospital
City
London
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kate Young, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Prior to study initiation, the study will be registered at www.clinicaltrials.gov. No later than six months after Follow-up completion, a study report will be completed and data displayed on www.clinicaltrials.gov. Study results will be submitted to the Clinical Trials Information System (CTIS) portal as soon as possible and no later than one year after the trial has ended. In addition, the anonymised data will be made public available through the Zenodo open data repository (CERN), or an equivalent public database.
IPD Sharing Time Frame
No later than one year after the trial has ended.

Learn more about this trial

Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis

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